Du Zhenchen, Saleh Ebraheem Abdu Musad, M Moharam M, Rab Safia Obaidur, Ballal Suhas, Singh Abhayveer, Sabarivani A, Sahoo Samir, Hsu Chou-Yi
China Three Gorges University, Yichang City, Hubei Province, China.
Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
Drug Dev Res. 2025 Nov;86(7):e70185. doi: 10.1002/ddr.70185.
Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzyme-triggered activation, these nanocarriers address a critical limitation of conventional chemotherapy, namely the lack of specificity that often leads to systemic toxicity and reduced therapeutic efficacy. Enzymes such as proteases, phospholipases, and oxidoreductases are frequently dysregulated in pathological tissues, providing endogenous signals that can be harnessed for site-specific drug release. Enzyme-responsive MNPs exploit these biochemical signatures by incorporating cleavable linkers, enzyme-sensitive coatings, or catalytic cascades, ensuring that therapeutic payloads are released selectively in tumor microenvironments, inflamed regions, or infection sites. Advances in nanoparticle synthesis have further enabled fine-tuning of magnetic cores, polymer shells, and functionalized surfaces, thereby enhancing stability, drug loading capacity, and responsiveness. Preclinical studies demonstrate substantial benefits, including enhanced tumor accumulation, alleviation of hypoxia, improved drug penetration through stromal barriers, and reduction of off-target toxicity. Applications extend beyond oncology to infectious diseases, where pathogen-derived enzymes activate antibiotic release, and to metabolic disorders, where glucose oxidase-based systems regulate insulin delivery. Despite these promising outcomes, translation to clinical practice is constrained by manufacturing challenges, variable enzyme expression, limited in vivo data, and stringent regulatory requirements. This review critically examines the principles, design strategies, release mechanisms, and biomedical applications of enzyme-responsive MNPs, while highlighting unresolved barriers and future directions. Ultimately, enzyme-responsive MNPs exemplify the potential of precision nanomedicine, offering a platform for highly adaptable, multimodal, and patient-tailored therapeutic interventions.
酶响应性磁性纳米颗粒（MNPs）是一类新兴的多功能药物递送系统，它将空间精确性与生化选择性结合在一起。通过将磁导向与酶触发激活相结合，这些纳米载体解决了传统化疗的一个关键局限性，即缺乏特异性，这往往导致全身毒性并降低治疗效果。蛋白酶、磷脂酶和氧化还原酶等酶在病理组织中经常失调，提供了可用于位点特异性药物释放的内源性信号。酶响应性MNPs通过结合可裂解连接体、酶敏感涂层或催化级联反应来利用这些生化特征，确保治疗有效载荷在肿瘤微环境、炎症区域或感染部位选择性释放。纳米颗粒合成技术的进步进一步实现了对磁芯、聚合物壳和功能化表面的精细调节，从而提高了稳定性、药物负载能力和响应性。临床前研究证明了其诸多益处，包括增强肿瘤蓄积、缓解缺氧、改善药物穿透基质屏障的能力以及降低脱靶毒性。其应用范围已从肿瘤学扩展到传染病领域（病原体衍生的酶可激活抗生素释放）以及代谢紊乱领域（基于葡萄糖氧化酶的系统可调节胰岛素递送）。尽管取得了这些有前景的成果，但向临床实践的转化仍受到制造挑战、酶表达可变、体内数据有限以及严格监管要求的限制。本综述批判性地研究了酶响应性MNPs的原理、设计策略、释放机制和生物医学应用，同时强调了尚未解决的障碍和未来方向。最终，酶响应性MNPs体现了精准纳米医学的潜力，为高度适应性、多模式和个性化的治疗干预提供了一个平台。
